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WO2022157207A1 - Marqueur biologique de la dysbiose intestinale, utile pour prédire la réponse d'un patient cancéreux à un médicament anti-pd1 - Google Patents

Marqueur biologique de la dysbiose intestinale, utile pour prédire la réponse d'un patient cancéreux à un médicament anti-pd1 Download PDF

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WO2022157207A1
WO2022157207A1 PCT/EP2022/051155 EP2022051155W WO2022157207A1 WO 2022157207 A1 WO2022157207 A1 WO 2022157207A1 EP 2022051155 W EP2022051155 W EP 2022051155W WO 2022157207 A1 WO2022157207 A1 WO 2022157207A1
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akkermansia
akk
ici
patient
cancer
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Lisa DEROSA
Romain DAILLERE
Laurence Zitvogel
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Everimmune
Institut Gustave Roussy (IGR)
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Everimmune
Institut Gustave Roussy (IGR)
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Priority to CA3204949A priority Critical patent/CA3204949A1/fr
Priority to US18/261,598 priority patent/US20240398876A1/en
Priority to KR1020237028121A priority patent/KR20230160233A/ko
Priority to EP22702191.2A priority patent/EP4281777A1/fr
Priority to AU2022210807A priority patent/AU2022210807A1/en
Priority to JP2023543101A priority patent/JP2024503710A/ja
Priority to CN202280021533.0A priority patent/CN116997798A/zh
Publication of WO2022157207A1 publication Critical patent/WO2022157207A1/fr
Priority to IL304335A priority patent/IL304335A/en
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/24—Mucus; Mucous glands; Bursa; Synovial fluid; Arthral fluid; Excreta; Spinal fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to the field of anticancer treatment.
  • the present invention concerns the role of the gut microbiota in the efficacy of immune checkpoints inhibitors (ICI)-based treatments and provides methods for determining if a patient is likely to benefit from an ICI-based treatment, more precisely, treatment comprising administration of an antibody directed against PD1 or PD-L1 .
  • ICI immune checkpoints inhibitors
  • the present invention provides a method for stratifying cancer patients according to their potential need of bacterial complementation before receiving an ICI-based treatment.
  • the present invention also provides a simple method for determining whether an individual has an intestinal dysbiosis.
  • ICI were approved in the first-line setting, either as monotherapy for patients with tumor PD-L1 expression > 50 % on tumor cells or in combination with platinum-doublet chemotherapy irrespectively of PD-L1 expression (Gandhi et al. 2018; Paz-Ares et al. 2018; Reck et al. 2016; Arielle Elkrief et al. 2020).
  • ICI only a minority (35%) of patients benefit from sustained response to ICI (Gadgeel et al. 2020).
  • the majority of NSCLC patients develop primary or secondary resistance, or occasional acceleration of the disease called “hyper-progression”(Ferrara et al. 2018).
  • current biomarkers of response to ICI are not satisfactory due to low sensitivity and specificity, and therefore, understanding mechanisms of resistance to ICI to identify robust biomarkers of resistance are urgently needed.
  • Akk 16S rRNA gene amplicon sequencing of 37 NSCLC patient feces, confirming that Akk was enriched in patients responding to ICI (Jin et al. 2019).
  • intestinal Akk also correlated with therapeutic responses (Daisley et al. 2020).
  • Akk has been associated in clinical specimens with low body mass index, fitness, general health and successful aging (as indicated by its presence in disease-free centenarians)(Santoro et al. 2018).
  • Akk supplementation reduces obesity (Zhou et al. 2020) and its comorbidities, palliates neurodegenerative disorders (Blacher et al. 2019) and counteracts progeria (Barcena et al. 2019). Therefore, Akk may be viewed as a potential master regulator of homeostasis in the metaorganism.
  • Akkermansia SGB9228 behave the same way as Akkermansia muciniphila, i.e., the presence of “normal levels” of A. muciniphila ( ⁇ . muciniphila' 0 ⁇ or Akkermansia SGB9228 (A SGB9228
  • A. muciniphila ⁇ . muciniphila' 0 ⁇ or Akkermansia SGB9228 (A SGB9228
  • a SGB9228 A SGB9228
  • the host needs a bacterial compensation for responding to an ICI-therapy.
  • the present invention pertains to an in vitro theranostic method to determine if a cancer patient is likely to be a good responder to an immune checkpoint inhibitor (ICI)-based therapy, comprising measuring, in a sample from said patient, the relative abundance of bacteria of the Akkermansia genus, for example Akkermansia muciniphila and/or Akkermansia SGB9228, wherein the presence of said Akkermansia below a predetermined threshold is indicative that the patient is likely to be a good responder to the ICI-based therapy.
  • ICI immune checkpoint inhibitor
  • the presence of normal levels of Akkermansia muciniphila (Akk low ) and/or of Akkermansia SGB9228 (Akk.SGB9228 low ) in the gut can be considered as a surrogate of host intestinal fitness and immune cell invaded microenvironment, thereby identifying patients who will likely respond to an ICI treatment, whereas Akkermansia muciniphila and/or of Akkermansia SGB9228 indicates dismal prognosis at supraphysiological levels that may reflect intestinal wound healing induced by ATB or other noxious factors.
  • the present invention thus also pertains to a method for determining if a cancer patient needs a bacterial compensation before administration of an ICI-based therapy, comprising measuring, in a sample from said patient, the relative abundance of Akkermansia, wherein:
  • a polymicrobial consortium especially, a complex polymicrobial consortium, i.e., a consortium of at least 5, preferably at least 7 and for example more than 10 different microbial strains
  • FMT fecal microbial transplant
  • Another aspect of the present invention is thus a method for determining if an individual has an intestinal microbiota dysbiosis, comprising measuring, in a sample from said individual, the relative abundance of Akkermansia, especially of Akkermansia muciniphila and/or Akkermansia SGB9228, wherein the presence of said Akkermansia below a predetermined threshold is indicative that there is no intestinal microbiota dysbiosis, and the absence of bacteria of the Akkermansia genus, especially of Akkermansia muciniphila and/or Akkermansia SGB9228, or their presence above the predetermined threshold, indicate intestinal microbiota dysbiosis.
  • the present invention also pertains to the use of polymicrobial consortia or FMT, especially with material from healthy individuals or from a cancer patient who successfully responded to the ICI-based therapy, for treating a cancer patient having an overrepresentation of the Akkermansia genus, especially of Akkermansia muciniphila and/or Akkermansia SGB9228 in his/her intestinal microbiota (prior to and in combination with the ICI-treatment).
  • Another aspect of the invention is a bacterial composition
  • bacteria of the Akkermansia genus especially of Akkermansia SGB9228 and/or Akkermansia muciniphila, for treating a cancer patient having no Akkermansia muciniphila and no Akkermansia SGB9228 in his/her intestinal microbiota (prior to and in combination with the ICI-treatment).
  • a lyophilized encapsulated strain of Akkermansia SGB9228 such as Akksp2261
  • favorable health-related species i.e Intestinimonas butyriciproducens, Odoribacter splanchnicus, Parasuterrella excrementihominis, Roseburia faecis.
  • the lower and upper hinges correspond to the first and third quartiles (the 25th and 75th percentiles).
  • the upper whisker extends from the hinge to the largest value no further than 1.5 * IQR from the hinge (where IQR is the inter-quartile range, or distance between the first and third quartiles).
  • the lower whisker extends from the hinge to the smallest value at most 1.5 * IQR of the hinge. Data beyond the end of the whiskers are called "outlying" points and are plotted individually.
  • Figure 2. Akk relative abundance represents a prognostic marker of ICI.
  • Akk undetectable Akk
  • Akk low Akk relative abundance between 0.035- 4.799%
  • Akk high >4.799% (77 th percentile).
  • the lower and upper hinges of boxplots correspond to the 25th and 75th percentiles, respectively.
  • the midline is the median.
  • the upper and lower whiskers extend from the hinges to the largest (or smallest) value no further than *1.5 interquartile range from the hinge, defined as the distance between the 25th and 75th percentiles.
  • D-F Kaplan-Meier curve and Cox regression multivariate analysis of overall survival in 338 NSCLC patients according to Akk relative abundance segregated in 3 groups (Akk", Akk low and Akk high ) (D) and considering PD-L1 expression (F).
  • Akk status was compared using the stratified log-rank test. P-values are one-sided with no adjustment. Cox logistic regression multivariate analysis of overall survival in 338 NSCLC patients according to Akk relative abundance segregated in 3 groups (Akk", Akk low and Akk high ) and all the other relevant clinical parameters (E). P-values were calculated using the Wald test including all covariates in the Cox Proportional Hazards Regression Model. Exact P-values are in Table 4. OS: overall survival. ECOG; eastern cooperative oncology group performance status. ATB: antibiotics. G.
  • Figure 3 Stratification of clinical outcome based on other components of the Akk -associated ecosystem.
  • A. Volcano plot (indicating Fold Change (FC) and p-values in Maaslin2 statistical analyses) to segregate taxonomic species (with a prevalence> 2.5%) according to their relative abundance in baseline fecal specimen of 338 patients based on their association with Akk. species significantly associated with or excluded from Akk' enriched ecosystems (Akk + , dark dots, Akk; underlined). P-values were calculated testing the null hypothesis and using a two-sides test.
  • Cox regression multivariate analysis for Kaplan Meier curves (right panels, The the trichotomic distribution was compared using the stratified log-rank test. P-values are onesided with no adjustment).
  • CR complete response.
  • PR partial response, SD; stable disease, PD; progressive disease.
  • Figure 4 Consort diagram describing the stool collection in the whole NSCLC ONCOBIOTICS cohort.
  • Chi-square test P-values are two-sided, with no adjustments made for multiple comparisons (A).
  • mice FMT of NSCLC patients (Table 6) segregated according to the presence or absence of Akk into MCA-205 tumor bearing C57BL/6 mice. Treatments are indicated by arrows (ATB, FMT, anti-PD-1 (ICI) mAbs, or isotype control mAbs (Iso)).
  • Akk isotype Ctl versus anti-PD-1 mAbs treated mice. Data are presented as mean values +/-SEM of tumor sizes within 6 animals/group.
  • Figure 7 Compositional taxonomic differences in stools of NSCLC patients segregated according to Akk relative abundance.
  • the lower and upper hinges of boxplots correspond to the 25th and 75th percentiles, respectively.
  • the midline is the median.
  • the upper and lower whiskers extend from the hinges to the largest (or smallest) value no further than *1.5 interquartile range from the hinge, defined as the distance between the 25th and 75th percentiles. P-values were calculated using a two-sided nonparametric Wilcoxon sum-rank test.
  • Beta-diversity using PCoA between Akk' and Akk low (B) and between Akk low and Akk hi9h (C) p-values were calculated using PERMANOVA with 999 permutations.
  • the PERMANOVA test compares groups of objects and tests the null hypothesis that the centroids and dispersion of the groups are equivalent.
  • the P-value is calculated by comparing the actual F test to that gained from (in this case 999) random permutations of the objects between the groups. If p ⁇ 0.05, the null hypothesis is disregarded and we conclude that the centroids and dispersion between the groups are not equivalent. D-E.
  • VIP Variable importance plot discriminant analysis of taxonomic stool composition according to Akk relative abundance, between Akk' versus Akk low (D) and Akk low versus Akk hi9h (E). Differences in bacterial prevalence and abundance in fold ratios are indicated in these VIP plots.
  • VIP Variable importance plot. * p ⁇ 0.05,** p ⁇ 0.01 , *** p ⁇ 0.001. P-values were calculated using a two-sided nonparametric Wilcoxon sum-rank test. # Multivariate analysis (ANCOM-BC/Maaslin2) with a false discovery rate (FDR) adjusted p-value ⁇ 0.2
  • Figure 8 Interaction between ATB and A.muciniphila on survival and microbiome composition.
  • A. Kaplan-Meier curve and Cox regression analysis of overall survival in the n 338 patients according to detectable versus undetectable Akk (Akk + and Akk") and ATB use (noATB: no exposure to ATB, ATB: antibiotics exposure within 2 months prior to ICI initiation). The Akk status and ATB use were compared using the stratified logrank test. P-values are one-sided with no adjustment.
  • B. Shannon diversity index representing stool alpha diversity in Akk + and Akk" groups of fecal specimen from patients exposed or not to ATB (N 338). The lower and upper hinges of boxplots correspond to the 25th and 75th percentiles, respectively. The midline is the median.
  • the upper and lower whiskers extend from the hinges to the largest (or smallest) value no further than *1.5 interquartile range from the hinge, defined as the distance between the 25th and 75th percentiles. P-values were calculated using a two-sided nonparametric Wilcoxon sum-rank test.
  • the lower and upper hinges of boxplots correspond to the 25th and 75th percentiles, respectively.
  • the midline is the median.
  • the upper and lower whiskers extend from the hinges to the largest (or smallest) value no further than *1.5 interquartile range from the hinge, defined as the distance between the 25th and 75th percentiles.
  • the test used was Kruskal-Wallis, two-sided, 5% level of significance. No adjustments were made for multiple comparisons.
  • Mean MCA-205 tumor sizes+/-SEM are depicted at day 12 after 4 therapeutic injections of anti-PD-1 mAbs, in each FMT groups (Akk + and Akk') supplemented or not with Akkermansia p2261 as well as in animals reared in SPF conditions (FMT-).
  • Each experiment comprising 6 mice/group and was performed at least 2 times for each FMT (Table 7) (B).
  • mice/group contained 6 mice/group and was performed 2-3 times for each tumor model (E, left panel). 16S rRNA sequencing of gene amplicons of stools harvested in recipient avatar tumor bearers at day 12 post-4 injections of anti-PD-1 Abs and 4 oral gavages with Akkermansia p2261 divided into light grey (R) and dark grey (NR) groups. VIP plot repartition of discriminant metagenomic species segregating groups of mice that responded to oral Akkermansia p2261 (R, light grey bars) or not (NR, dark grey bars). (E, right panel). Asterisks represent significant Mann-Whitney II test without FDR at 10%. * p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.001. P-values were calculated using a two-sided nonparametric Wilcoxon sum-rank test. Adjustments for multiple comparisons were not made.
  • Akk relative abundance represents a prognostic marker of ICI.
  • FIG. 11 Effect of strains of Akkermansia on the therapeutic response to checkpoint blockade in SPF mice versus mice having received FMT from non-responder patients.
  • Tumor size shown for ATB-treated mice receiving fecal microbial transplantation from one non-responder patient alone followed by inoculation of MCA-205 sarcomas and PD-1 blockade (n 6 per group).
  • a representative experiment is shown. Compensation of dysbiosis was attempted by addition of Akkermansia strain 2261 , 5801 , 5126, 4531 or 3284.
  • Anova statistics *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001.
  • FIG 12 IL-12 production by bone marrow-derived dendritic cells (BM-DC) exposed to several commensals (MOI 1 :20).
  • Bone marrow-dendritic cells were obtained by in vitro culture in GM-CSF/IL-4 and were stimulated for 1 hr with live strains of Akkermansia (aligned in the x axis), which were subsequently neutralized by appropriate ATB, prior to harvesting supernatants at 24hrs to monitor IL-12p70 concentrations by commercial ELISA.
  • Anova statistics *p ⁇ 0.05, **p ⁇ 0.01 , ***p ⁇ 0.001.
  • Figure 13 qPCR-based identification of Akkermansia mucinphila strains (5801 , 5126 and 5145) or Akkermansia SGB9228 strains (4531 and 2261) using primers recognizing either both species of Akkermansia (SGB9226/9228, top left panel), Akkermansia muciniphila strains (Akkermansia SGB9226, top right panel), Akkermansia SGB9228 strains (bottom left panel), or primers specific for the p2261 strain (bottom right panel).
  • gut microbiota (formerly called gut flora or microflora) designates the population of microorganisms living in the intestine of any organism belonging to the animal kingdom (human, animal, insect, etc.). While each individual has a unique microbiota composition (60 to 80 bacterial species are shared by more than 50% of a sampled population on a total of 400-500 different bacterial species/individual), it always fulfils similar main physiological functions and has a direct impact on the individual’s health:
  • gut microbiota plays in the normal functioning of the body and the different functions it accomplishes, it is nowadays considered as an “organ”.
  • organ it is an “acquired” organ, as babies are born sterile; that is, intestine colonisation starts right after birth and evolves afterwards.
  • gut microbiota starts at birth. Sterile inside the uterus, the newborn’s digestive tract is quickly colonized by microorganisms from the mother (vaginal, skin, breast, etc.), the environment in which the delivery takes place, the air, etc. From the third day, the composition of the intestinal microbiota is directly dependent on how the infant is fed: breastfed babies’ gut microbiota, for example, is mainly dominated by Bifidobacteria, compared to babies nourished with infant formulas.
  • the composition of the gut microbiota evolves throughout the entire life, from birth to old age, and is the result of different environmental influences. Gut microbiota’s balance can be affected during the ageing process and, consequently, the elderly have substantially different microbiota than younger adults.
  • composition at a species level is highly personalised and largely determined by the individuals’ genetic, environment and diet.
  • the composition of gut microbiota may become accustomed to dietary components, either temporarily or permanently.
  • Japanese people, for example, can digest seaweeds (part of their daily diet) thanks to specific enzymes that their microbiota has acquired from marine bacteria.
  • Dysbiosis a disequilibrium between potentially “detrimental” and “beneficial” bacteria in the gut or any deviation to what is considered a “healthy” microbiota in terms of main bacterial groups composition and diversity.
  • Dysbiosis may be linked to health problems such as functional bowel disorders, inflammatory bowel diseases, allergies, obesity and diabetes. It can also be the consequence of a treatment, such as a cytotoxic treatment or an antibiotic treatment.
  • an “immune checkpoint inhibitor”, or “ICI”, a “drug blocking an immune checkpoint”, or “immune checkpoint blocker” or “immune checkpoint blockade drug” designates any drug, molecule or composition which blocks an immune checkpoint.
  • it encompasses anti-PD1 antibodies, anti-PD-L1 antibodies (such as Atezolizumab or Durvalumab), anti-CTLA-4 antibodies and anti-PD-L2 antibodies. More particularly, it can be an anti-PD1 monoclonal antibody such as Nivolumab or Pembrolizumab.
  • an “anti-PD1/PD-L1 Ab-based therapy” herein designates any drug that antagonizes PD1 or PD-L1.
  • the currently used drugs antagonizing PD1 or PD-L1 are monoclonal antibodies, other molecules specifically binding to PD1 , PD-L1 could be used for the development of future ICI such as, for example, antibody fragments or specifically designed aptamers.
  • the phrase “anti-PD1/PD-L1 Ab-based therapy” encompasses any therapy with active molecules that antagonize PD1 or PD-L1.
  • cancer means all types of cancers.
  • the cancers can be solid or non solid cancers.
  • Non limitative examples of cancers are carcinomas or adenocarcinomas such as breast, prostate, ovary, lung, pancreas or colon cancer, sarcomas, lymphomas, melanomas, leukemias, germ cell cancers and blastomas.
  • the immune system plays a dual role against cancer: it prevents tumor cell outgrowth and also sculpts the immunogenicity of the tumor cells. Drugs blocking an immune checkpoint can hence be used to treat virtually any type of cancer.
  • the methods according to the invention are potentially useful for patients having a cancer selected amongst adrenal cortical cancer, anal cancer, bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancers (e.g.
  • osteoblastoma osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma, lymphoma, multiple myeloma), brain and central nervous system cancers (e.g. meningioma, astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, Schwannoma, germinoma, craniopharyngioma), breast cancer (e.g.
  • ductal carcinoma in situ infiltrating ductal carcinoma, infiltrating lobular carcinoma, lobular carcinoma in situ, gynecomastia
  • Castleman disease e.g. giant lymph node hyperplasia, angiofollicular lymph node hyperplasia
  • cervical cancer colorectal cancer
  • endometrial cancers e.g. endometrial adenocarcinoma, adenocanthoma, papillary serous adenocarcinoma, clear cell
  • esophagus cancer gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoid tumors (e.g.
  • choriocarcinoma chorioadenoma destruens
  • Hodgkin's disease non-Hodgkin's lymphoma, Kaposi's sarcoma
  • kidney cancer e.g. renal cell cancer
  • laryngeal and hypopharyngeal cancer liver cancers (e.g. hemangioma, hepatic-adenoma, focal nodular hyperplasia, hepatocellular carcinoma)
  • lung cancers e.g. small cell lung cancer, non-small cell lung cancer
  • mesothelioma plasmacytoma
  • nasal cavity and paranasal sinus cancer e.g.
  • esthesioneuroblastoma midline granuloma
  • nasopharyngeal cancer neuroblastoma
  • oral cavity and oropharyngeal cancer ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g. embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma, nonmelanoma skin cancer), stomach cancer, testicular cancers (e.g.
  • thyroid cancers e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma, thyroid lymphoma
  • vaginal cancer e.g. uterine leiomyosarcoma
  • the method according to the invention can be used for predicting and optimizing a patient’s response to a medicament targeting an immune checkpoint, wherein the patient has a cancer selected from the group consisting of metastatic melanoma, non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), mesothelioma, bladder cancer, renal cell carcinoma, head and neck cancers, oesophageal and gastric cancers, rectal cancers, hepatocarcinoma, sarcoma, Wilm's tumor, Hodgkin lymphoma, ALK-neuroblastoma, (hormone refractory) prostate cancers and GIST.
  • NSCLC non-small cell lung carcinoma
  • SCLC small cell lung cancer
  • mesothelioma bladder cancer
  • renal cell carcinoma head and neck cancers
  • oesophageal and gastric cancers rectal cancers
  • hepatocarcinoma sarcoma
  • Wilm's tumor Hodgkin lymph
  • the present invention pertains to an in vitro theranostic method of determining if a cancer patient is likely to be a good responder to an immune checkpoint inhibitor (ICI)-based therapy, comprising measuring, in a sample from said patient, the relative abundance of Akkermansia muciniphila and/or Akkermansia SGB9228, wherein the presence of Akkermansia muciniphila and/or Akkermansia SGB9228 below a predetermined threshold (“superior threshold”) is indicative that the patient is likely to be a good responder to the ICI-based therapy.
  • ICI immune checkpoint inhibitor
  • the present invention thus relates to an in vitro theranostic method of determining if a cancer patient is likely to be a good responder to an immune checkpoint inhibitor (ICI)-based therapy, comprising measuring, in a sample from said patient, the relative abundance of the Akkermansia genus, wherein the presence of bacteria of the Akkermansia genus below a predetermined threshold (“superior threshold”) is indicative that the patient is likely to be a good responder to the ICI-based therapy.
  • ICI immune checkpoint inhibitor
  • the presence of Akkermansia muciniphila at supraphysiologic levels correlates with an overall survival significantly lower than the overall survival of patients whose feces is bereft of Akkermansia muciniphila, itself lower that the overall survival of patients exhibiting Akkermansia muciniphila at a level comprised between an inferior threshold (corresponding to the detection limit in the reported experiments) and a superior threshold, hereafter designated as the “predetermined threshold”.
  • threshold An example of threshold that can be used as “predetermined threshold” in the frame of the invention is disclosed in the experimental part below.
  • the skilled artisan can adapt or refine this threshold, depending on the technique used to measure the relative abundance of Akkermansia muciniphila and/or Akkermansia SGB9228 and/or of the Akkermansia genus (for example, metagenomics, quantitative PCR, hybridization on a microarray or pyrosequencing), the species of Akkermansia which is(are) detected, the specific pathology of the patient, the patient’s food habits, the specific ICI used for the treatment and other possible factors.
  • the threshold to be considered when performing the above method can be predetermined by measuring the relative abundance of Akkermansia muciniphila and/or Akkermansia SGB9228, and/or of the Akkermansia genus in a representative cohort of individuals having the same cancer as the patient for whom a prognostic is sought, and choosing as threshold the value of the 75 th percentile.
  • This threshold can be different for Akkermansia muciniphila and for Akkermansia SGB9228.
  • the values of the relative abundances of Akkermansia muciniphila obtained in healthy volunteers (from available literature) and from three cohorts of metastatic patients diagnosed with melanoma or with kidney or lung cancers are shown below.
  • the “presence of Akkermansia muciniphila below a predetermined threshold” thus means that Akkermansia muciniphila is present at a level between two thresholds: an inferior threshold (close to 0, typically ⁇ 0.001 , for example 0.0005) and a superior threshold (the “predetermined threshold” as described above).
  • an inferior threshold close to 0, typically ⁇ 0.001 , for example 0.0005
  • a superior threshold the “predetermined threshold” as described above.
  • the predetermined threshold corresponds to a relative abundance between 1 and 10%, for example between 3 and 6.5%.
  • the predetermined threshold is selected so that it is between the 75 th and the 77 th percentile. It can be selected by grid search algorithm. With the cohort used in the experimental part below, the selected cutoff (predetermined threshold) corresponds to 4.79 (77th percentile), measurement error 4.75 +/-0.1. A predetermined threshold of 4.75 +/-0.1 can thus be used as superior threshold when performing the method of the invention. Of course, as already mentioned, this threshold can be refined or adapted by the skilled person, by routine experiments.
  • the ICI-based therapy is an anti-PD1/PD-L1/PD-L2 Ab-based therapy (such as, but not limited to Nivolumab, Pembrolizumab, Atezolizumab and Durvalumab) or an anti-CTLA4 Ab-based therapy (such as, but not limited to Ipulimumab), or a combination thereof.
  • an anti-PD1/PD-L1/PD-L2 Ab-based therapy such as, but not limited to Nivolumab, Pembrolizumab, Atezolizumab and Durvalumab
  • an anti-CTLA4 Ab-based therapy such as, but not limited to Ipulimumab
  • the present invention is particularly useful for patients suffering from non small cell lung cancer (NSCLC) or kidney cancer, or from any cancer amenable to PD1/PDL-1 or CTLA4 blockade.
  • NSCLC non small cell lung cancer
  • CTLA4 blockade any cancer amenable to PD1/PDL-1 or CTLA4 blockade.
  • the methods of the invention can be advantageously performed for cancer patients who suffer from any cancer amenable to immunotherapy, such as, but not limited to: melanoma; renal cell carcinoma (RCC); Non small-cell lung carcinoma (NSCLC); Head and Neck squamous cell carcinoma (HNSCC); Merkel cell carcinoma (MCC); bladder cancer; Hodgkin lymphoma; squamous cell carcinoma; breast cancer, especially triple-negative breast cancer; gastric cancer; small-cell lung carcinoma; primary mediastinal B-cell lymphoma; cervical cancer; hepatocellular carcinoma; esophageal cancer; cancers with MicroSatellite Instability; endometrial cancer and any cancer with a high tumor mutational burden (TMB-H cancers).
  • RCC renal cell carcinoma
  • NSCLC Non small-cell lung carcinoma
  • HNSCC Head and Neck squamous cell carcinoma
  • MCC Merkel cell carcinoma
  • bladder cancer Hodgkin lymphoma; squamous cell carcinoma; breast cancer, especially triple-
  • the present invention is useful in situations where the ICI-based therapy is administered as first-line therapy or second-line therapy or beyond (3 rd , 4 th line).
  • the predetermined threshold is chosen such that the presence of Akkermansia muciniphila and/or Akkermansia SGB9228, and/or of the Akkermansia genus above this threshold is indicative of dismal prognosis despite ICI-based therapy.
  • the present invention pertains to a method for in vitro determining if a cancer patient needs a bacterial compensation before administration of an ICI-based therapy, and to provide the physician with information related to the type of compensation that can improve the patient’s likelihood to respond to the treatment.
  • this method comprises measuring, in a sample from said patient, the relative abundance of Akkermansia muciniphila and/or Akkermansia SGB9228, and provides the physiclian with the following guide:
  • the method for in vitro determining if a cancer patient needs a bacterial compensation before administration of an ICI-based therapy comprises measuring, in a sample from said patient, the relative abundance of the Akkermansia genus, and provides the physiclian with the following guide:
  • the predetermined threshold corresponds to a relative abundance of Akkermansia muciniphila and/or Akkermansia SGB9228 and/or the Akkermansia genus between 1 and 10%, for example between 3 and 6.5% or any other predetermined threshold as described above.
  • the ICI- based therapy is an anti-PD1/PD-L1/PD-L2 Ab-based therapy or an anti-CTLA4 Ab-based therapy or a combination thereof (as described above).
  • the method according to the present invention is particularly useful for in vitro determining if a cancer patient suffering from non small cell lung cancer (NSCLC), especially from non-squamous NSCLC needs a bacterial compensation before administration of an ICI-based therapy, as well as for in vitro determining if a cancer patient suffering from kidney cancer or from any cancer amenable to PD1/PD-L1/PD-L2 and/or CTLA4 blockade needs a bacterial compensation before administration of an ICI-based therapy.
  • the method is performed before an ICI-based therapy administered as first-line therapy, to assess whether the patient needs a bacterial compensation for improving his/her chances of responding to this therapy.
  • the method is performed before an ICI-based therapy administered as or second-line therapy or beyond (3 rd , 4 th line).
  • Another aspect of the present invention is thus a method for determining if an individual has an intestinal microbiota dysbiosis, comprising measuring, in a sample from said patient, the relative abundance of Akkermansia muciniphila and/or Akkermansia SGB9228 and/or the Akkermansia genus, wherein the presence of Akkermansia muciniphila and/or Akkermansia SGB9228 and/or the Akkermansia genus below a predetermined threshold is indicative that there is no intestinal microbiota dysbiosis.
  • the predetermined threshold corresponds to a relative abundance between 1 and 10%, for example between 3 and 6.5% or any other predetermined threshold as described above.
  • the sample from said patient or individual can be a feces sample or a sample from the colon or ileal luminal content of said patient or individual, or a mucosal biopsy from said patient or individual.
  • the present invention relates to the use of a fecal microbial composition in the treatment of a cancer patient having an overrepresentation of Akkermansia muciniphila and/or Akkermansia SGB9228 and/or the Akkermansia genus in his/her intestinal microbiota, especially to restore a healthy microbiota before administering an ICI-based therapy, to improve the patient’s chances of responding to the treatment.
  • the inventors have demonstrated that although the presence of Akkermansia muciniphila and/or Akkermansia SGB9228 predicts favorable clinical outcome when present at levels compatible with homeostasis, an overrepresentation of Akkermansia muciniphila and/or Akkermansia SGB9228 indicates dismal prognosis. This overrepresentation can result from intestinal wound healing induced by ATB or other noxious factors and is indicative of dismal prognosis despite ICI-treatment.
  • the fecal microbial composition originates from a healthy individual or from a cancer patient who successfully responded to the ICI-based therapy.
  • the present invention thus relates to the use of a bacterial composition comprising Akkermansia muciniphila or Akkermansia SGB9228, in the treatment of a cancer patient having no Akkermansia muciniphila and no Akkermansia SGB9228 in his/her intestinal microbiota, especially to improve the patient’s chances of responding to an ICI-based treatment.
  • the Akkermansia bacteria are from the strain deposited at the Collection de souches de I’Unite des Rickettsies (CSLIR) under the reference CSLIR P2261.
  • This strain initially identified as Akkermansia muciniphila, was recently reclassified in the Akkermansia SGB9228 candidate species.
  • the Akkermansia bacteria are from the strain deposited at the Collection de souches de I’Unite des Rickettsies (CSLIR) under the reference CSLIR 4531.
  • the fecal microbial composition or the bacterial composition according to the invention can be particularly useful if they are administered before and/or the ICI-based therapy, particularly in combination with a treatment with an anti-PD1/PD-L1 Ab-based therapy or an anti-CTLA4 Ab-based therapy or a combination thereof.
  • the abovedescribed microbial composition or bacterial composition is used in the treatment of a patient who suffers from non small cell lung cancer (NSCLC), especially from non- squamous NSCLC, or from kidney cancer or any cancer amenable to PD1/PDL-1 or CTLA4 blockade, as detailed above.
  • NSCLC non small cell lung cancer
  • the abovedescribed microbial composition or bacterial composition is used in the treatment of a patient who suffers from non small cell lung cancer (NSCLC), especially from non- squamous NSCLC, or from kidney cancer or any cancer amenable to PD1/PDL-1 or CTLA4 blockade, as detailed above.
  • NSCLC non small cell lung cancer
  • the abovedescribed microbial composition or bacterial composition is used in the treatment of a patient who received an ICI-based therapy as first-line therapy or second-line therapy or beyond.
  • Akkermansia muciniphila can be measured by quantitative PCR using the following primers:
  • Example 1 Intestinal Akkermansia muciniphila predicts clinical response to PD1 blockade in advanced non-small cell lung cancer patients
  • NCT04567446 a multicentric prospective observational study designed to evaluate the impact of the microbiome composition in the clinical outcome of advanced NSCLC patients treated with anti-PD-(L)1.
  • Eligible patients received ICI following progression on platinum-based chemotherapy regimens, either with nivolumab or atezolizumab regardless of PD-L1 expression or with pembrolizumab if PD-L1>1 %.
  • Treatment modalities' the number of Pembrolizumab (every other 21 days) or Nivolumab (every other 15 days) or Atezolizumab (every other 21 days) injections received was 4+/- 2 at 8-12 weeks and was 20+/- 4 at 12 months.
  • V1 pre-ICI
  • V2 before the second ICI injection
  • V3 at 3 months post-ICI
  • V4 at 6 months post-ICI
  • SGBs Akkermansia candidate species or species-level genome bins
  • MucT A. muciniphila.
  • msp_0025 corresponds to SGB9226, and used its relative abundance values as a proxy for A. muciniphila in MetaOMineR.
  • a full description of both DNA purification and metagenomic pipelines is available in Derosa et al (Lisa Derosa et al. 2020). Starting from abundance matrices, only taxa that were present in at least 2.5% of all samples were considered, and then raw data were normalized and standardized (Sci-Kit-learn version 0.20.3).
  • mice All animal experiments were carried out in compliance with French and European laws and regulations.
  • the local institutional animal ethics board (Ministere de la Recherche, de I'Enseignement Superieur er de I'lnnovation) approved all mice experiments (permission numbers: 2016-049-4646, 2018-020-510263031 v3).
  • Mice avatar studies have been approved by the regulatory animal facility local and national committees (Ministere de la Recherche, de I'Enseignement Superieur et de I'lnnovation) (Everimmune #13366-2018020510263031 v3, APAFIS#17530-201811413352738 v2 (03/2019-03/2024). APAFIS# 21378-201907080848483459).
  • mice Female C57BI/6 and BALB/c were purchased from Harlan (France) and Janvier (France), respectively. Mice were used between 8 and 16 weeks of age housed in specific pathogen-free conditions (SPF). All mouse experiments were performed at the animal facility in Gustave Roussy Cancer Campus where animals were housed in SPF conditions. Cell culture, reagents and tumor cell lines. MC38, MCA-205 and B16F10 (syngeneic from C57BL/6 mice), and 4T1 cell lines (syngeneic from BALB/c mice) were purchased from ATCC.
  • 4T 1 , MCA-205 and MC38 cells were cultured in RPMI 1640 containing 10% FCS, 2mM L-glutamine, 100 Ul/rnl penicillin/streptomycin, 1 mM sodium pyruvate and MEM non-essential amino. All reagents were purchased from Gibco-lnvitrogen (Carlsbad, CA, USA). B16F10 and CT26 cells were cultured in DMEM containing containing 10% FCS, + 100 Ul/ml penicillin/streptomycin + non-essential amino acid. All cell lines were cultured at 37°C with 5% CO2 and regularly tested to be free of mycoplasma contamination.
  • mice were respectively implanted with 0.8 x 10 6 MCA-205, 1.0 x 10 6 MC38/CT26 or 3 x 10 5 B16F10 cells subcutaneously.
  • Syngeneic BALB/c mice were implanted with 3 x 10 5 4T1 cells subcutaneously.
  • tumor- implanted mice were treated intraperitoneally (i.p.) when tumors reached 20 to 40 mm 2 in size with anti-PD-1 mAbs (250pg/mouse; clone RMP1-14, lot 695318A1) or isotype control (clone 2A3, lot 686318F1). Mice were injected 4 times at 3-day intervals with anti- PD-1 mAbs. Tumor length and width were routinely monitored every 3 times per week by means of a caliper. All antibodies were purchased from BioXcell, NH, US.
  • mice were treated with an antibiotic solution (ATB) containing ampicillin (1 mg/ml), streptomycin (5mg/ml), and colistin (1 mg/ml) (Sigma- Aldrich) added in the drinking water of mice.
  • ATB antibiotic solution
  • Antibiotic activity was confirmed by cultivating fecal pellets resuspended in BHI+15% glycerol at 0.1 g/ml on COS (Columbia Agar with 5% Sheep Blood) plates for 48h at 37°C in aerobic and anaerobic conditions.
  • mice received 3 days of ATB before undergoing fecal microbial transplantation the next day by oral gavage using animal feeding needles.
  • FMT experiments Fecal microbiota transfer (FMT) was performed by thawing fecal material. Two hundred pL of the suspension was then transferred by oral gavage into ATB pre-treated recipient (as described above). In addition, another 100pL was applied on the fur of each animal. Two weeks after FMT, tumor cells were injected subcutaneously and mice were treated with anti-PD-1 mAbs or isotype control as previously explained.
  • MCA-205 fibrosarcomas because it is normally -in SPF eubiotic mice- sensitive to anti-PD-1 Ab and has been used as a reference mouse model in our previous avatar experiments reported in (Routy, Le Chatelier, et al. 2018) and (Lisa Derosa et al.
  • Murine meta-analysis ( Figure 6E-F).
  • 6-8 groups including 6 mice/group
  • the growth kinetics of orthotopic MCA-205 sarcomas and other tumors such as MC38 colon cancer (syngeneic from C57BL/6 mice), or 4T1 breast or CT26 colon tumors (syngeneic from BALB/c mice) or B16 (melanoma) were monitored in avatar mouse models (Routy, Gopalakrishnan, et al. 2018).
  • FMT fecal microbial transplants
  • LEfSe was used to identify the taxonomic changes segregating R versus NR to exogenous Akkermansia p2261. These species were compared with the bacteria featuring in human stools described in Figure 4 and Figure 3A.
  • mice Itentification of the bacterium was performed using a Matrix-Assisted Laser Desorption/lonization Time of Flight (MALDI- TOF) mass spectrometer (Microflex LT analyser, Bruker Daltonics, Germany). Colonization of ATB pre-treated mice was performed by oral gavage with 100 pl of suspension containing 1 x 10 8 bacteria obtained from a suspensions of 10 9 CFU/mL using a fluorescence spectrophotometer (Eppendorf) at an optical density of 600 nm in PBS. Five bacterial gavages were performed for each mouse: the first 24h before the first injection of anti-PD-1 mAbs and, subsequently, four times on the same day of ICI.
  • MALDI- TOF Matrix-Assisted Laser Desorption/lonization Time of Flight
  • Mouse fecal DNA extraction and microbiota characterization Feces were harvested in each mouse and group for metagenomics between 7 and 14 days after start of immunotherapy. Samples were stored at -80°C until processing. Preparation and sequencing of mouse fecal samples was performed at IHU Mediterranee Infection, Marseille, France. Briefly, DNA was extracted using two protocols. The first protocol consisted of physical and chemical lysis, using glass powder and proteinase K respectively, then processing using the Macherey-Nagel DNA Tissue extraction kit (Duren, Germany). The second protocol was identical to the first protocol, with the addition of glycoprotein lysis and deglycosylation steps. The resulting DNA was sequenced, targeting the V3-V4 regions of the 16S rRNA gene.
  • Raw FASTQ files were analyzed with Mothur pipeline v.1 .39.5 for quality check and filtering (sequencing errors, chimerae) on a Workstation DELL T7910 (Round Rock, Texas, United States).
  • Raw reads were filtered and clustered into Operational Taxonomic Units (OTUs), followed by elimination of low-populated OTUs (till 5 reads) and by de novo OTU picking at 97% pair- wise identity using standardized parameters and SILVA rDNA Database v.1.19 for alignment.
  • a prevalence threshold of > 2.5% was implemented for statistical analyses on recognized OTUs, performed with Python v3.8.2.
  • Exploratory analysis of p-diversity was calculated using the Bray-Curtis measure of dissimilarity and represented in Principal Coordinate Analyses (PCoA), along with methods to compare groups of multivariate sample units (analysis of similarities - ANOSIM, permutational multivariate analysis of variance - PERMANOVA) to assess significance in data points clustering.
  • PCoA Principal Coordinate Analyses
  • ANOSIM and PERMANOVA were automatically calculated after 999 permutations, as implemented in SciKit-learn package vO.4.1.
  • PLS-DA Partial Least Square Discriminant Analysis
  • VIP Variable Importance Plot
  • Raw sequencing counts were estimated from specieslevel MetaPhlAn 3 relative abundances by multiplying these values by the total number of reads for each sample and these were used in ANCOM-BC (v.1.0.1) with default parameters, a library size cutoff of 500 reads and no structural zero detection.
  • Masslin2 (v.1 .4.0) was run using Logit transformed relative abundances that were normalized with total-sum-scaling (TSS) and using the variable of interest as a fixed effect.
  • the optimal cutoff for each bacterial species to define different prognosis groups was obtained with grid search algorithm based on the multivariate Cox model to take into account the potential confounding factors (age, sexe,).
  • the grid was defined for each species by the percentiles of the distribution of the non-zero prevalence values.
  • the cutoff corresponding to the model with the better Akaike information criterion (AIC, lower is better) was selected as the optimal cutoff.
  • mice In mice, all tumor growth curves were analyzed using software developed in Kroemer’s laboratory: https://kroemerlab.shinyapps.io/TumGrowth/. Between-group comparisons of mice, global comparison were performed using Kruskall-Wallis test, post- hoc multiple comparisons using Dunn's test. Finally, natural tumor growth data deriving fom mice experiments (6 mice per experiment) were averaged for each timepoint (TO to T8), then longitudinally normalized on the first timepoint, in order to have a common starting value of 1.
  • mice were implanted with syngeneic orthotopic MCA-205 sarcomas (representative tumor model for sensitivity to anti-PD-1 antibodies as previously described (Routy, Le Chatelier, et al. 2018; Lisa Derosa et al. 2020)) and later subjected to PD-1 blockade (Figure 5C-E).
  • syngeneic orthotopic MCA-205 sarcomas representative tumor model for sensitivity to anti-PD-1 antibodies as previously described (Routy, Le Chatelier, et al. 2018; Lisa Derosa et al. 2020)
  • PD-1 blockade Figure 5C-E
  • ATB tended to reduce the alpha diversity of the Akk + group ( Figure 8B-C).
  • ATB exposure enriched the Akk + group in Gammaproteobacteria (E. coli), Clostridia class (Clostridium bolteae, Ruthenibacterium lactatiformens), and H2S producing bacteria (Bilophila wadsworthia) (not show), as already described (Lisa Derosa et al. 2020) at the expense of health-associated bacteria (C. aerofaciens, D. longicatena, D. formicigenerans, Eubacterium sp. CAG 38)(Routy, Gopalakrishnan, et al. 2018; Benevides et al. 2017) also over-represented in the Akk + group who did not take ATB (not shown).
  • Gammaproteobacteria E. coli
  • Clostridia class Clostridia class (Clostridium bolteae, Ruthenibacterium lactatiformen
  • mice we concatenated all tumor models syngeneic of BALB/c (CT26, 4T1) and C57BL/6 (B16F10, MCA-205 MC38) mice that were first transferred with stools from 29 individual NSCLC patients (Tablex S3) and then treated with anti-PD-1 antibodies (Figure 9A) and collected recipient feces pre-and postoral feeding with Akkermansia p2261.
  • mice transferred with Akk' human fecal material exhibited a phenotype of tumor resistance to PD-1 blockade but were rescued by Akkermansia p2261 when Akkermansia p2261 could shift the microbiome towards the favorable A associated collateral ecosystem.
  • the intestinal residence of Akk was a proxy of richness of the gut ecosystem, as shown by the association of Akk at a relative abundance within the 77 th percentile (Akk low ⁇ 4.799%), with stool alpha diversity (Shannon diversity index).
  • ATB promoted the overabundance of Akk (Akk hi9h ) above the 77 th percentile level associated with poor prognosis. Indeed, ATB use doubled the proportion of individuals presenting a stool Akk hi9h phenotype. This phenotypic trait of overabundance of Akk > 4.799 was associated with a dominance of the Clostridium species (C. bolteae, C. innocuum, C. asparagiforme, C. scindens, C. symbosium) belonging to clusters IV and XlVa of the genus Clostridium, known to maintain IL-10 producing Treg in colonic lamina intestinal (Atarashi et al. 2011).
  • Clostridium species C. bolteae, C. innocuum, C. asparagiforme, C. scindens, C. symbosium
  • Akk hi9h overabundance of Akk > 4.799 (Akk hi9h ) was associated with a shorter overall survival than “normal” relative abundance of Akk ⁇ 4.799, possibly reflecting an underlying pathophysiological disorder of the intestinal barrier in these advanced cancer patients.
  • High relative proportions or subdominance of A. muciniphila in the ecosystem has been associated with pathophysiological failures (such as anorexia nervosa (Ruusunen et al. 2019), GVHD (Shono et al. 2016), Aging (van der Lugt et al. 2019), dysmetabolism (Depommier et al. 2019b), HIV infection (Ouyang et al.
  • Akk relative abundance could represent a reliable biomarker of favorable or dismal prognosis for patients receiving immunotherapy with PD-1 blockade. It may be of utmost importance to risk-stratified l-O patients based on shot-gun metagenomics (rather than by 16S rRNA) sequencing to precisely quantify the relative abundance of Akk in addition to ATB use, and PD-L1 expression in prospective trials including NSCLC patients and designed to discover optimal biomarkers.
  • Example 2 Intestinal Akkermansia SGB9228 predicts clinical response to PD1 blockade in advanced non-small cell lung cancer patients and boosts the efficacy of PD-1 blockade in preclinical models
  • strains displayed high similarity by 16S rRNA gene sequences, with 16S rRNA gene sequences of strains in different candidate species never diverging by more than 2%.
  • Akkermansia candidate species differed strongly in their prevalence across hosts.
  • A. muciniphila is by far the most prevalent candidate species across all hosts, being detected in 34% of adult humans and reaching a maximum prevalence of 54% in laboratory-held mice. The other candidate species were detected at lower prevalence ( ⁇ 25%) across all hosts.
  • Akkermansia p2261 is a strain of Akkermansia belonging to Akkermansia SGB9228:
  • Akkermansia p2261 a deep characterization of Akkermansia p2261 has been performed to elucidate the phylogroup and respective phenotypic traits of Akkermansia p2261.
  • Whole-genome phylogeny of the metagenome-assembled genomes was performed, and it was determined that Akkermansia p2261 belongs to the species Akkermansia SGB9228, which is distinct from Akkermansia muciniphila.
  • Akkermansia muciniphila type strain genome provided by the American Type Culture Collection (ATCC) was compared to Akkermansia p2261 genome.
  • the completeness of assembled isolates was evaluated using CheckM’s lineage_wf function (Parks et al., Genome Res. 2015).
  • the assembled contigs were then processed and Parsnp was used as the core genome aligner to align the core genome of multiple microbial genomes.
  • the average nucleotide identity (AN Im) between isolates was assessed using MUMrner (Kurtz et al., Genome Biol. 2004).
  • Average identity via MLIMer indicates the nucleotide identity percentage between Akkermansia muciniphipla ATCC BAA 835 type strain genome and the G1284 reference (Akkermansia p2261). A higher average identity indicates greater similarity between genomes.
  • BMDCs bone marrow derived dendritic cells
  • Primers have been designed for the specific identification of Akkermansia muciniphila (SGB9226) and Akkermansia SGB9228 species ( Figure 13).
  • the primers were designed with Primer-BLAST (Ye et al., BMC Bioinformatics, 2012) and the specificity was checked using representative genomes desposited on RefSeq.
  • the relative abundances of Akkermansia muciniphila and/or Akkermansia SGB9228 can be measured by quantitative PCR using the following primers:
  • Embelin increases VCAM-1 levels on the endothelium, producing lymphocytic infiltration and antitumor immunity till Oncoimmunology 9 (1). Consulte le 12 decembre 2020. https://doi.Org/10.1080/2162402X.2020.1838812.
  • Gut bacteria Akkermansia is associated with reduced risk of obesity: evidence from the American Gut Project Wales Nutrition & Metabolism 17 (1): 90. https://doi.Org/10.1186/S12986-020-00516-1 .

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Abstract

La présente invention concerne le domaine des traitements anticancéreux. En particulier, la présente invention concerne le rôle du microbiote intestinal dans l'efficacité des traitements à base d'inhibiteurs de point de contrôle immunitaire (IPCI) et fournit des méthodes pour déterminer si un patient est susceptible de bénéficier d'un traitement à base d'IPCI, plus précisément un traitement comprenant l'administration d'un anticorps dirigé contre PD1 ou PD-L1. La présente invention concerne une méthode permettant de classer les patients cancéreux en fonction de leur besoin potentiel de complémentation bactérienne avant de recevoir un traitement à base d'IPCI. La présente invention concerne également une méthode simple permettant de déterminer si un individu présente une dysbiose intestinale.
PCT/EP2022/051155 2021-01-19 2022-01-19 Marqueur biologique de la dysbiose intestinale, utile pour prédire la réponse d'un patient cancéreux à un médicament anti-pd1 Ceased WO2022157207A1 (fr)

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Application Number Priority Date Filing Date Title
CA3204949A CA3204949A1 (fr) 2021-01-19 2022-01-19 Marqueur biologique de la dysbiose intestinale, utile pour predire la reponse d'un patient cancereux a un medicament anti-pd1
US18/261,598 US20240398876A1 (en) 2021-01-19 2022-01-19 Biological marker of intestinal dysbiosis, useful for predicting the response of a cancer patient to an anti-pdi drug
KR1020237028121A KR20230160233A (ko) 2021-01-19 2022-01-19 항-pd1 약물에 대한 암 환자의 반응을 예측하는데 유용한장내 디스바이오시스의 생물학적 마커
EP22702191.2A EP4281777A1 (fr) 2021-01-19 2022-01-19 Marqueur biologique de la dysbiose intestinale, utile pour prédire la réponse d'un patient cancéreux à un médicament anti-pd1
AU2022210807A AU2022210807A1 (en) 2021-01-19 2022-01-19 Biological marker of intestinal dysbiosis, useful for predicting the response of a cancer patient to an anti-pd1 drug
JP2023543101A JP2024503710A (ja) 2021-01-19 2022-01-19 抗ｐｄ１薬に対するがん患者の応答の予測に役立つ、腸内ディスバイオシスの生物学的マーカー
CN202280021533.0A CN116997798A (zh) 2021-01-19 2022-01-19 可用于预测癌症患者对抗pd1药物的反应的肠道生态失调的生物标志物
IL304335A IL304335A (en) 2021-01-19 2023-07-09 A biomarker for intestinal dysbiosis that is effective in predicting a cancer patient's response to an anti-pd1 drug

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WO2024094817A1 (fr) 2022-11-04 2024-05-10 Institut Gustave Roussy Score prédictif de résultat d'immunothérapie anticancéreuse basé sur l'analyse écologique du microbiote intestinal
EP4414461A1 (fr) * 2023-02-10 2024-08-14 Bash Biotech Inc Procédé de détection d'un risque accru d'avoir ou de développer une rcc
WO2024200517A1 (fr) * 2023-03-28 2024-10-03 Zoe Limited Empreintes microbiomiques et alimentaires, et procédés comprenant la modification directive de la composition du microbiome
WO2025083271A1 (fr) 2023-10-19 2025-04-24 Institut Gustave Roussy Composition bactérienne comprenant des espèces akkermansia, pour améliorer la réponse à une thérapie par lymphocytes t car

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024082648A1 (fr) * 2022-10-22 2024-04-25 首都医科大学附属北京胸科医院 Système de détection de typage intestinal
WO2024094817A1 (fr) 2022-11-04 2024-05-10 Institut Gustave Roussy Score prédictif de résultat d'immunothérapie anticancéreuse basé sur l'analyse écologique du microbiote intestinal
EP4414461A1 (fr) * 2023-02-10 2024-08-14 Bash Biotech Inc Procédé de détection d'un risque accru d'avoir ou de développer une rcc
WO2024165758A1 (fr) * 2023-02-10 2024-08-15 Bash Biotech Inc Procédé de détection d'un risque accru de présenter ou de développer un carcinome rénal cancéreux
WO2024200517A1 (fr) * 2023-03-28 2024-10-03 Zoe Limited Empreintes microbiomiques et alimentaires, et procédés comprenant la modification directive de la composition du microbiome
WO2025083271A1 (fr) 2023-10-19 2025-04-24 Institut Gustave Roussy Composition bactérienne comprenant des espèces akkermansia, pour améliorer la réponse à une thérapie par lymphocytes t car

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AU2022210807A9 (en) 2024-10-17
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